Sequential hydrozirconation/Pd-catalyzed cross coupling of acyl chlorides towards conjugated (2E,4E)-dienones

Dienones are challenging building blocks in natural product synthesis due to their high reactivity and complex synthesis. Based on previous work and own initial results, a new stereospecific sequential hydrozirconation/Pd-catalyzed acylation of enynes with acyl chlorides towards conjugated (2E,4E)-dienones is reported. We investigated a number of substrates with different alkyl and aryl substituents in the one-pot reaction and showed that regardless of the substitution pattern, the reactions lead to the stereoselective formation (≥95% (2E,4E)) of the respective dienones under mild conditions. It was found that enynes with alkyl chains gave higher yields than the corresponding aryl-substituted analogues, whereas the variation of the acyl chlorides did not affect the reaction significantly. The synthetic application is demonstrated by formation of non-natural and natural dienone-containing terpenes such as β-ionone which was available in 4 steps and 6% overall yield.

However, these reactions face multiple disadvantages such as limited substrate scope, use of hazardous solvents and harsh reaction conditions such as high temperatures or acidic/basic conditions, which might be incompatible with existing functional groups and/or the stereochemical integrity [18,22]. Especially in natural product synthesis, dienone functional groups suffer from isomerization and polymerization [23]. Therefore, a late stage introduction of dienone units is advantageous [24].
Negishi extended Crombie's work on dienamides and prepared dienoates 15 by hydrozirconation of terminal alkynes 16 followed by Pd-catalyzed cross coupling with enoates 17 [55,56]. A repetitive approach gave rise to oligoenoates [57]. Hydrozirconations were also combined with carbonylations to install carbonyl groups. For example, the sequential hydrozirconation/ carbonylation of propargylic ethers 18 reported by Donato [58] [59,60], Cox revealed that terminal alkynes 16 could be converted to enones 20 by hydrozirconation followed by Pd-catalyzed acylation with acyl chlorides 21 [61]. The substrate scope required aryl units at either alkyne or acid chloride unit. Recently, we could extend this method to alkyl-substituted alkynes 16 and acetyl chloride (22), providing enone building blocks 23 for the synthesis of clifednamides [54,62]. The addition of Schwartz's reagent proceeds as a syn-addition affording (E)-alkenylzirconocenes 24 from terminal alkynes [28]. Based on these precedents from the literature, we surmised that it might be possible to establish a related approach to convert (E)-enynes 25 via hydrozirconation to the corresponding (E)-alkenylzirconocenes 24 and subsequent Pd-catalyzed acylation to conjugated (2E,4E)-dienones 27.

Results and Discussion
The investigation of the hydrozirconation/acylation sequence required first the synthesis of (E)-enynes 25 via Corey-Fuchs reaction (Table 1) [63]. Starting from different substituted, (E)configurated enals 28, the respective dibromo-olefines 29 were formed by reaction of 28 with 4 equiv of PPh 3 and 2 equiv of CBr 4 for 3 h. Treating 29 with 2.2 equiv of n-butyllithium for 1 h resulted in the desired enynes 25a-e in yields up to 77%. Unfortunately, in the case of nitro-substituted enyne 25d only 4% were isolated due to rapid decomposition and instability issues ( Table 1, entry 4).
With enynes 25a-e in hand, the influence of solvent, reaction temperature, time, and Pd source on the hydrozirconation and subsequent coupling were examined by using phenylenyne 25a and benzoyl chloride (26a) as benchmark substrates. The results are summarized in Table 2. For example, treatment of phenylenyne 25a with 1.12 equiv of commercially available Schwartz reagent in THF at 50 °C for 1 h and subsequent treatment with benzoyl chloride (26a) in the presence of 5 mol % of Pd(PPh 3 ) 2 Cl 2 for 20 h at room temperature yielded 49% of the desired (2E,4E)-configurated dienone 27a (Table 2, entry 1).
No other stereoisomer was detected in the crude product, suggesting an all E-configuration ≥95% (via 1 H NMR). Accordingly, the internal double bond in 25a stayed unaffected whereas the triple bond, as expected, selectively formed the double bond with (E)-configuration. Note that a reaction temperature of 50 °C is required in the first step of the sequence to obtain rapid solubility of the Schwartz reagent in the solvent but is not necessarily required in the subsequent steps. When the reaction was carried out in benzene, CH 2 Cl 2 or dioxane, much lower yields of 28%, 31%, and 8%, respectively, were obtained ( Table 2, entries 2-4). Toluene gave the best yield with 55% ( Table 2, entry 5). Therefore, further optimization steps were performed with toluene. By running the reaction at room temperature and decreased reaction times (3 h), the yield decreased to 28% (  Trapping experiments of the in situ-formed (E)-alkenylzirconocene 24 revealed quantitative conversion of the starting material 25a and only traces of chain walking (less than 4%) (for details see Supporting Information File 1, chapter 2.1).
To optimize the second step of the reaction sequence, several Pd complexes were tested in the reaction of 25a with 26a. However, the yields of the dienone 27a decreased considerably, when (Ph 3 P) 2 PdCl 2 was replaced by other Pd complexes (Table 3, entries 2-5). In particular, (AntPhos) 2 Pd(dba) and (XPhos) 2 Pd(dba) were catalytically inactive (Table 3, entries 6  and 7). Furthermore, in situ-formed Schwartz reagent was found to be less effective as compared to the use of isolated Cp 2 Zr(H)Cl and thus further experiments in this direction were abandoned. In order to explore the substrate scope of the sequential reaction, different enynes 25 and acid chlorides 26 were studied (Table 4). Fortunately, all desired products 27 were formed in ≥95% (2E,4E)-configuration (via 1 H NMR). First, phenylenyne 25a (R 1 = Ph) was chosen as the starting material and reacted with different acid chlorides 26a-s (Table 4). While 4-methylbenzoic acid chloride (26b) behaved similarly to benzoyl chloride (26a) giving 27ab in a slightly higher yield of 57% (Table 4, entry 2), the yield of 27ac dropped to only 17% upon use of the corresponding 2-methylbenzoyl chloride (26c) ( Table 4, entry 3). By attaching further electron-donating or electron-withdrawing groups at the benzoyl chloride 26 (Table 4, entries 4-8), the yields of the desired products decreased to 10-30% compared to 27ab. Benzoyl chlorides carrying multiple substituents, such as 2,4,6-trichlorobenzoyl chloride (26i), 3,5-dinitrobenzoyl chloride (26j), 3,4,5trimethoxybenzoyl chloride (26k), and pentafluorobenzoyl chloride (26l) were also tested, but did not give any trace of the respective dienone 27 (Table 4, entries 9-12). Consequently, the hydrozirconation and Pd-catalyzed cross coupling is rather sensitive towards both electron-donating and electron-withdrawing substituents at the benzoyl moiety of 25. The analysis of crude 1 H NMR spectra of 27 indicated decomposition and side product formation (for details see Supporting Information File 1, chapter 2.2). Unfortunately, due to the poor amount of side products, these compounds could not be isolated by chromatography and HPLC purification steps. However, GC-MS analysis of the crude product of one exemplary dienone 27ac (with only 17% yield) indicated only decomposition in the reaction sequence.
Next, the variation of enynes 25 was investigated (Table 4, entries 20-24). The sequence again showed its sensitivity towards both electron-donating and electron-withdrawing substituents on the phenyl group of the enyne 25. The reaction of 4-methylphenylenyne 25b with benzoyl chloride (26a, Table 4, entry 20) led to the desired product 27ba in only 9% yield. With 4-chlorophenylenyne 25c as well as 4-nitrophenylenyne 25d, 17% and 10% yield of product were obtained, respectively (Table 4, entries 21 and 22). In contrast, aliphatic enynes showed promising results. Due to their high volatility, we limited the following experiments to enyne 25e with a long alkyl chain. Reaction of 25e with benzoyl chloride (26a) gave 34% of the dienone 27ea (Table 4, entry 23), whereas the reaction with acetyl chloride (22) gave 65% yield of the desired product 27eq (Table 4, entry 24).
In the following series of experiments, substituted enynes 25f-o were employed, which were synthesized beforehand via Corey-Fuchs reaction [63] starting from (E)-configurated enals 28a and 28f forming 29a and 29f in 95% and 86% yield, respectively (Scheme 4). The dibromo-olefines 29a and 29f were then each treated with 2.2 equiv of n-butyllithium for 1 h to form enynes 25a and 25f in 48% yield. Whereas treating 29a and 29f with 2.2 equiv of n-butyllithium and 5 equiv of alkyl iodide led to isolation of the alkyl-substituted compounds 25g-j with up to 54% yield. The reaction of 29a and 29f with TBAF·H 2 O gave bromoenynes 25m in 13% and 25n in 52% yield. Deprotonation of 25a and 25f with n-butyllithium and reaction with ethyl chloroformate yielded 25k and 25l in 55% and 82% yield, respectively.
With the substituted enynes 25f-o in hand, the hydrozirconation and cross coupling was investigated. Therefore, 4-phenyl-3-methylenyne 25f reacted with benzoyl chloride (26a) smoothly to the dienone 27fa in 55% yield (Table 5, entry 1). In agreement with the previous observations, methyl substituents at the aryl moiety and/or the alkyne terminus compromised the yield (Table 5, entries 3 and 10). Furthermore, dienones 27g,i-n with bromo-, ethyl-, and ethoxycarbonyl substituents were not accessible through this approach.
As the sequential hydrozirconation/Pd-catalyzed acylation worked reasonably well for aliphatic substrates, we surmised that terpene-derived enynes might be suitable starting materials for natural product synthesis. For this purpose, two terpene enynes 25p and 25q were synthesized and investigated in the hydrozirconation/acylation sequence (Scheme 5).

Conclusion
Based on initial results by Cox on the sequential hydrozirconation/Pd-catalyzed acylation of alkynes with acyl chlorides, the scope was extended towards a novel stereospecific dienone synthesis starting from enynes 25 and acyl chlorides 26. Our results revealed that the reaction sequence formed selectively (2E,4E)dienones 27 (≥95% (2E,4E)) under mild conditions, as the acetylene moiety in substrates 25 only reacted to the (E)-olefin while the internal double bond stayed unaffected. Compared to the reaction with benzoyl chloride (26a), which led to the desired dienone 27aa in 55% yield, aliphatic or conjugated acyl chlorides did not affect the reaction with phenylenyne 25a significantly. However, in case of substituted aromatic acyl chlorides, both electron-donating and electron-withdrawing substituents at the aryl unit, decreased the yield remarkably up to 10%. The same effect was observed in the reaction of substituted phenylenynes 25b-d with benzoyl chloride (26a).
The best results were obtained in the reaction of aliphatic enyne 25e with benzoyl chloride (26a) and acetyl chloride (22) in yields of 34% and 65%, respectively. Methyl substitution on the alkene functionality of enyne 25 did not affect the yield, however, methyl substitution at the alkyne terminus significantly decreased the yield. Finally, non-natural and natural dienonecontaining terpenes were synthesized such as β-ionone (3), which was available in 4 steps (6% overall yield). Thereby, the synthetic utility was demonstrated by a late-stage introduction of the dienone unit by a hydrozirconation/acylation sequence.